US5811556AExpiredUtility

Preparation of mibefradil via a naphthalenylacetic acid

37
Assignee: ROCHE COLORADO CORPPriority: Apr 30, 1997Filed: Apr 14, 1998Granted: Sep 22, 1998
Est. expiryApr 30, 2017(expired)· nominal 20-yr term from priority
Inventors:Peter J. HarringtonJim-Wah Wong
C07D 235/14
37
PatentIndex Score
1
Cited by
19
References
19
Claims

Abstract

A method of preparing 2- 2-{ 3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate comprises contacting (6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid or an activated derivative of (6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid with 3-(1H-benzimidazol-2-yl)propyl!methylamine to form N- 3-(1H-benzimidazol-2-yl) propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3 ,4-tetrahydronaphthalen-2-yl)-N-methylacetamide, reducing this to 2- 2-{ 3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-ol, and treating the 2- 2-{ 3-(1H-benzimidazol-2-yl) propyl!-methylamino}ethyl!-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol with methoxyacetic acid or an activated derivative of methoxyacetic acid. The invention is particularly applicable to the preparation of mibefradil, (1S,2S)-2- 2-{ 3-(1H-benzimidazol-2-yl)propyl!methylamino}-ethyl!-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate, and its dihydrochloride salt. N- 3-(1H-benzimidazol-2yl)propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide is new.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
       1. N- 3-(1H-Benzimidazol-2-yl)propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide, as an individual isomer or as a racemic or non-racemic mixture of isomers. 
     
     
       2. The compound of claim 1 that is (1S,2S)-N- 3-(1H-Benzimidazol-2-yl) propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide. 
     
     
       3. A method of preparing N- 3-(1H-benzimidazol-2-yl)propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide comprising contacting (6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid or an activated derivative of (6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid with  3-(1H-benzimidazol-2-yl)propyl!methylamine. 
     
     
       4. The method of claim 3 for preparing (1S,2S)-N- 3-(1H-benzimidazol-2-yl) propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide comprising contacting (1S,2S)-(6-fluoro-2-hydroxy-1 -isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl) acetic acid or an activated derivative of (1S,2S)-(6-fluoro-2-hydroxy-l-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)acetic acid with  3-(1H-benzimidazol-2-yl)propyl!methylamine. 
     
     
       5. The method of claim 3 where an activated derivative of the (6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)acetic acid is contacted with the  3 -(1H-benzimidazol-2-yl)propyl!methylamine. 
     
     
       6. The method of claim 5 where the activated derivative of (6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)acetic acid is the mixed anhydride of (6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)acetic acid with trimethylacetic acid. 
     
     
       7. The method of claim 6 where the mixed anhydride of (6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)acetic acid with trimethylacetic acid is formed by the reaction of (6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid with a trimethylacetyl halide in the presence of an organic base. 
     
     
       8. The method of claim 7 where the trimethylacetyl halide is trimethylacetyl chloride and the organic base is triethylamine. 
     
     
       9. A method of preparing 2- 2-{ 3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol comprising treating N- 3-(1H-benzimidazol-2-yl)propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide with a reducing agent. 
     
     
       10. The method of claim 9 for preparing (1S,2S)-2- 2-{ 3-(1H-benzimidazol-2-yl) propyl!methylamino}ethyl!-6-fluoro-1-isopropyl-1 ,2,3,4-tetrahydronaphthalen-2-ol comprising treating (1S,2S)-N- 3-(1H-benzimidazol-2-yl)propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide with a reducing agent. 
     
     
       11. The method of claim 9 where the reducing agent is a metal hydride. 
     
     
       12. The method of claim 11 where the reducing agent is sodium bis(2-methoxyethoxy)-aluminum hydride. 
     
     
       13. The method of claim 9 further including the step of contacting the thus-formed 2- 2-{ 3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-ol with methoxyacetic acid or an activated derivative of methoxyacetic acid to prepare 2- 2-{ 3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate. 
     
     
       14. The method of claim 10 further including the step of contacting the thus-formed (1S,2S)-2- 2-{  3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-ol with methoxyacetic acid or an activated derivative of methoxyacetic acid to prepare (1S,2S)-2- 2-{ 3-(1H-benzimidazol-2-yl)propyl!methylamino}-ethyl!-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate. 
     
     
       15. The method of claim 13 where the methoxyacetic acid or activated derivative of methoxyacetic acid is methoxyacetyl chloride, and the step of contacting occurs in the presence of a base in an aprotic solvent. 
     
     
       16. The method of claim 13 further including the step of forming an acid addition salt of the 2- 2-{ 3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl methoxyacetate. 
     
     
       17. The method of claim 16 where the acid addition salt is the dihydrochloride salt. 
     
     
       18. The method of claim 17 where the step of forming the dihydrochloride salt comprises reacting the 2- 2-{ 3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl methoxyacetate with a solution of hydrogen chloride in a lower alkanol. 
     
     
       19. The method of claim 18 where the lower alkanol is ethanol.

Cited by (0)

No later patents cite this yet.

References (0)

No backward citations on record.